Preparation of levalbuterol hydrochloride

ABSTRACT

Provided are processes for the preparation of (R)-SLB.D-DBTA salt and levalbuterol hydrochloride. Also provided are levalbuterol hydrochloride degradation products and processes for preparing them. Pharmaceutical compositions comprising at least one levalbuterol hydrochloride of the invention and at least one pharmaceutically-acceptable excipient are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 11/133,721, filed May 20, 2005, which claims the benefits of U.S.Provisional Patent Application Nos. 60/573,025, filed May 20, 2004,60/577,979, filed Jun. 7, 2004, 60/646,803, filed Jan. 25, 2005,60/577,819, filed Jun. 7, 2004, 60/583,777, filed Jun. 28, 2004,60/583,642, filed Jun. 28, 2004, 60/587,673, filed Jul. 13, 2004 and60/632,625, filed Dec. 2, 2004, the contents of all of which areincorporated herein by reference.

FIELD OF THE INVENTION

The invention encompasses processes for the preparation of(R)-SLB.D-DBTA salt, and levalbuterol hydrochloride. The invention alsoencompasses levalbuterol hydrochloride degradation products andprocesses for preparing them. Also provided are pharmaceuticalcompositions comprising at least one levalbuterol hydrochloride of theinvention and at least one pharmaceutically-acceptable excipient.

BACKGROUND OF THE INVENTION

Activation of β₂-adrenergic receptors on airway smooth muscle leads tothe activation of adenylcyclase and to an increase in the intracellularconcentration of cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Thisincrease in cyclic AMP leads to the activation of protein kinase A,which inhibits the phosphorylation of myosin and lowers intracellularionic calcium concentrations, resulting in relaxation. Levalbuterolrelaxes the smooth muscles of the airways, from the trachea to theterminal bronchioles. Levalbuterol acts as a functional antagonist torelax the airway irrespective of the spasmogen involved thus protectingagainst all bronchoconstrictor challenges. Increased cyclic AMPconcentrations are also associated with the inhibition of release ofmediators from mast cells in the airway. The chemical name forlevalbuterol HCl is(R)-α¹-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanolhydrochloride.

Levalbuterol HCl has been synthesized using a variety of syntheticschemes. For example, Great Britain patent No. 1298494 disclosessynthesizing levalbuterol first by crystallizing the alkyl acetate ofthe 4-carboxylate derivative (Formula 1) using ditolyltartaric acid andisolating the selected crystalline fraction. Thereafter, the crystalundergoes debenzylation deprotection, followed by ester reduction toyield levalbuterol.

Several patents report synthetic routes using enantiomeric separation,however, the synthetic routes result in low yields of theenantiomerically pure product. Optically pure levalbuterol wassynthesized by the borane-methylsulfide reduction of theenantiomerically pure precursor (Formula 2) as described in U.S. Pat.No. 5,399,765. The reaction dissolved a mixture of enantiomers of methyl5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate and achiral acid selected from (−)-di-toluoyl-L-tartaric acid and(+)-di-toluoyl-D-tartaric acid in methanol, upon cooling onestereoisomer crystallized, which was separated, and recrystallized as adiastereomer from methanol, the diastereomer was separated, treated withbase, and upon reduction formed optically active levalbuterol.

U.S. Pat. No. 5,442,118 discloses the synthesis of optically pure (R) or(S) levalbuterol by the asymmetric reduction of α-iminoketonesprecursors. In particular, levalbuterol is synthesized by the reductionwith borane-methylsulfide complex in the presence of chiraloxazaborolidines as catalysts.

During the synthesis of levalbuterol, D-dibenzoyltartaric acid (D-DBTA)or D-ditoluoyltartaric acid (D-DTTA) have been used for enantiomericseparation. Typically, during the enantiomeric separation, at least oneof the alcohol, ester, or amine functional groups on levalbuterol isprotected. The protecting group is typically a benzyl group, which afterseparation is removed to yield levalbuterol. See U.S. Pat. No. 5,545,745and WO 95/32178.

The prior art has separated levalbuterol enantiomers using 4-benzyllevalbuterol. See WO 02/48090. The synthesis uses tartaric acid forenantiomeric separation and once the (L) tartaric acid salt is formedand one enantiomer separated, then the salt is debenzylated to yieldeither the (R) or (S) isomer of salbutamol as a sulphate salt.

Other publications have separated levalbuterol derivatives, such as WO99/42460, by forming the ketal derivative of levalbuterol prior toenantiomeric separation with an enantiomer of di-O-benzoyl tartaric acidor di-O-(p-toluoyl)-tartaric acid. Thus, after enantiomeric separationof the ketal, the derivative is hydrolyzed to yield the desiredlevalbuterol enantiomer. The process continuously recycles the undesiredenantiomer in the derivatize, resolve, and hydrolyze cycle to furtherenhance the overall yield of the desired enantiomer.

In Chinese patent No. 1,273,966, enantiomers of racemic salbutamol areseparated using tartaric acid, D-DBTA, D-DTTA, or a mixture thereof as aresolving agent. In the examples provided, the ratios of reactionsolvent to salbutamol were at least about 14 ml/g. Levalbuterolhydrochloride is isolated by acid-base work-up or by solid-solidtransformation in acetone. In one example, the salt of (R)-levalbuterolD-dibenzoyltartaric acid is treated with potassium carbonate in waterand an organic solvent, such as ethylacetate. After phase separation andextraction of the aqueous layer, the organic layer is dried and thelevalbuterol free base is precipitated overnight. Levalbuterol HCl issynthesized by acid displacement from (R)-levalbuterolD-dibenzoyltartaric acid salt suspended in acetone and the addition ofan ether solution of HCl.

Despite the many attempts of the prior art to synthesizeenantiomerically pure levalbuterol, novel synthetic processes oflevalbuterol are still needed to reduce the steps necessary forsynthesis while maximizing synthetic yield without sacrificing compoundpurity.

SUMMARY OF THE INVENTION

The invention encompasses processes for preparing (R)-SLB.D-DBTAcomprising preparing a mixture of racemic salbutamol in a first C₁-C₄alcohol; adding D-dibenzoyltartaric acid to the mixture; crystallizingand isolating crude (R)-SLB.D-DBTA; and recrystallizing the crude(R)-SLB.D-DBTA in a second C₁-C₄ alcohol to obtain the (R)-SLB.D-DBTA,wherein the first or second alcohol is present in an amount of about 2ml/g to about 7.5 ml/g of the salbutamol. In one embodiment, the firstor second alcohol is methanol. The crystallizing step is performed byseeding with (R)-SLB.D-DBTA. In the process, the D-dibenzoyltartaricacid is present in an amount of about 0.5 mol to about 1.3 molequivalents of the salbutamol.

Another embodiment of the invention encompasses enantiomerically pure(R)-SLB.D-DBTA salt having an enantiomeric excess of at least about99.8%.

Yet another embodiment of the invention encompasses processes forpreparing levalbuterol hydrochloride comprising preparing a first slurryof (R)-SLB.D-DBTA in a first solvent; adding hydrochloric acid to thefirst slurry to form crude levalbuterol hydrochloride; isolating thecrude levalbuterol hydrochloride; preparing a second slurry of the crudelevalbuterol hydrochloride in a second solvent; and isolating thelevalbuterol hydrochloride. In the process, the first or second solventis at least one of C₃-C₁₀ ester, C₃-C₁₀ ketone, C₃-C₁₀ ether, C₁-C₄alcohol, C₆-C₁₂ aromatic hydrocarbon, tetrahydrofuran,dimethylcarbonate, dimethylsulfoxide, dimethylformamide,dichloromethane, or acetonitrile. In particular, the first solvent is atleast one of ethylacetate, acetone, tetrahydrofuran, dimethylcarbonate,acetonitrile, toluene, xylene, methanol, ethanol, isopropanol,dimethylsulfoxide, or dimethylformamide. The second solvent is at leastone of methanol, ethanol, isopropanol, ethylacetate, butyl acetate, DMF,acetone, toluene, isopropyl ether, diethyl ether, methyl tert butylether, dichloromethane, or acetonitrile. Optionally, the second solventfurther comprises water, for example, acetone and water. In oneembodiment, the hydrochloric acid is present in an amount of about 1 molto about 1.3 mol equivalents of the (R)-SLB.D-DBTA. The slurry may becooled at a temperature of about −20° C. to about 110° C. In theprocess, the HCl may be added as a solution or a gas.

Another embodiment of the process encompasses where the first or secondsolvent is at least one C₃-C₆ ester or a mixture of at least one C₁-C₄alcohol and C₃-C₆ ester. Preferably, the alcohol is methanol and theester is ethylacetate. Also, the first or second solvent has an alcoholto ester ratio of about 15:85 by volume.

Yet another embodiment of the invention encompasses levalbuterolhydrochloride characterized by at least one of an enantiomeric excess ofat least about 99.8%; having less than about 1700 ppm of residual C₁-C₄alcohol; or having a pH of at least about 4.3 in 1% aqueous solution atroom temperature. Preferably, the residual alcohol is methanol. In oneembodiment, the pH is about 4.5 to about 7.

Yet another embodiment of the invention encompasses levalbuterolhydrochloride characterized by at least one of having less than about0.15% by area HPLC of total at least one of Compound A, Compound B, orCompound C; having less than about 0.10% by area HPLC of total unknownimpurities; or having less than about 0.25% by area HPLC of totalimpurities including Compound A, Compound B, and Compound C, after beingstored for three months at 40° C. and 75% relative humidity.

Another embodiment of the invention encompassesN-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(hydroxymethyl)phen-1-yl-ethanamine,Compound B, having the following structure:

Another embodiment of the invention encompassesN-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(methoxymethyl)phen-1-yl)-ethanamine,or Compound C having the following structure:

Yet another embodiment of the invention encompasses pharmaceuticalcompositions comprising a therapeutically effective amount of thelevalbuterol hydrochloride of the invention and at least onepharmaceutically-acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses enantiomerically pure(R)-salbutamol.D-dibenzoyltartrate (“(R)-SLB.D-DBTA”) salt, levalbuterolhydrochloride in enantiomerically pure form, and processes for theirpreparation. Typically, the processes require fewer steps and result inhigher yields and/or optical purity than conventional processes. Theinvention also encompasses polymorphs of levalbuterol and compoundssynthesized during the preparation of levalbuterol.

In particular, the invention encompasses processes for separatingracemic salbutamol enantiomers using D-dibenzoyltartrate (“D-DBTA”) as aresolving agent. The processes do not require the protection of thealcohol or amine functional groups and require significantly lesssolvent than conventional processes to prepare enantiomerically pure(R)-SLB.D-DBTA. The use of less solvent is advantageous especially inindustrial scale production due to cost, efficiency, and pollutionconsiderations. Furthermore, the processes yield after twocrystallization steps (R)-SLB.D-DBTA salt in 40-43% yield and anenantiomeric excess of at least about 99.8%. Enantiomerically pure(R)-SLB.D-DBTA salt is useful for preparing levalbuterol hydrochloridewith high optical purity. Not to be limited by theory, it is believedthat the (R)-SLB.D-DBTA salt converts to levalbuterol hydrochloride in asolid-solid transformation.

The process for preparing (R)-SLB.D-DBTA salt comprises preparing amixture of racemic salbutamol in a first C₁-C₄ alcohol; addingD-dibenzoyltartaric acid to the mixture; crystallizing and isolatingcrude (R)-SLB.D-DBTA salt; and recrystallizing the crude (R)-SLB.D-DBTAsalt in a second C₁-C₄ alcohol to obtain the (R)-SLB.D-DBTA salt.

The first alcohol is present in any amount sufficient to dissolve theracemic salbutamol and D-dibenzoyltartaric acid at reflux. Preferably,the alcohol is present in an amount of about 2 ml/g to about 7.5 ml/g ofthe racemic salbutamol, more preferably about 2 ml/g to about 5 ml/g,and most preferably about 4 ml/g to about 5 ml/g. C₁-C₄ Alcoholsinclude, but are not limited to, at least one of methanol, ethanol,propanol, isopropanol, butanol, isobutanol, or tert-butanol. Thepreferred alcohol is methanol.

The D-dibenzoyltartaric acid may be present in any amount sufficient toform the (R)-SLB.D-DBTA salt. Preferably, the D-dibenzoyltartaric acidis present in an amount of about 0.5 mol to about 1.3 mol equivalents ofthe salbutamol, and more preferably about 1 mol equivalent.

The mixture of racemic salbutamol and a first alcohol may be heated toform a solution, preferably at a temperature of at least about 50° C.More preferably, the mixture is heated at about reflux temperature.Depending on the solvent used, the solution may be heated at othersuitable temperatures as long as the racemic salbutamol andD-dibenzoyltartaric acid are sufficiently dissolved. For example, wherethe reaction solvent is methanol, the mixture is preferably heated atabout 60° C. to about 65° C.

The crude (R)-SLB.D-DBTA may be crystallized by methods such as seeding.Seeding may be carried out as soon as the solution is cool enough not todissolve the seeding material. Preferably, the solution is cooled beforeseeding at a temperature below reflux, and more preferably at atemperature of about 50° C.

Preferably, the solution is seeded with (R)-SLB.D-DBTA having anenantiomeric excess of at least about 99%. After seeding, the solutionis cooled at a temperature that permits crystal formation withoutcausing the solution to freeze. The solution may be cooled at any ratethat facilitates formation of the (R)-SLB.D-DBTA salt. Preferably, thesolution is cooled at a temperature of about −20° C. to about 10° C.,more preferably at about −10° C. to about 10° C., and most preferably atabout −5° C. The solution may be cooled to a preferred temperatureimmediately after seeding, or cooled within a period of about 15 hours.The crude (R)-SLB.D-DBTA salt may be isolated by filtration and washedwith additional solvent prior to recrystallization.

The second C₁-C₄ alcohol used for recrystallization can be the same asthe alcohol used during the reaction of salbutamol andD-dibenzoyltartaric acid, or it can be different. The preferred alcoholfor recrystallization is methanol. The second alcohol is present in anyamount sufficient to crystallize (R)-SLB.D-DBTA salt. Preferably, thealcohol is present in an amount of about 2 ml/g to about 5 ml/g of theracemic salbutamol, and more preferably, in about 3 ml/g to about 4ml/g.

The second alcohol is heated, preferably at reflux, to dissolve thecrude (R)-SLB.D-DBTA salt and form a solution. The solution may betreated with charcoal and filtered, after which the solution is furtherheated, followed by cooling, to precipitate the enantiomerically pure(R)-SLB.D-DBTA salt. The precipitated (R)-SLB.D-DBTA salt is preferablyisolated by filtration and washed with additional solvent.

The invention encompasses enantiomerically pure (R)-SLB.D-DBTA. As usedherein, “enantiomerically pure” refers to an enantiomeric excess of atleast about 99.8%. Enantiomeric excess, as well as chemical purity, aredetermined by area percent HPLC.

The invention also encompasses processes for preparing levalbuterolhydrochloride. The process comprises preparing a first slurry of(R)-SLB.D-DBTA in a first solvent; adding hydrochloric acid to the firstslurry to form crude levalbuterol hydrochloride; and isolating crudelevalbuterol hydrochloride. Optionally, the process may further comprisepreparing a second slurry of the crude levalbuterol hydrochloride in asecond solvent; and isolating the levalbuterol hydrochloride.

A suitable first solvent is one in which levalbuterol hydrochloride isinsoluble and DBTA is soluble. The first solvent includes, but is notlimited to, at least one linear or branched C₃-C₆ ester, C₃-C₁₀ ketone,C₃-C₁₀ ether, C₁-C₄ alcohol, C₆-C₁₂ aromatic hydrocarbon,dimethylcarbonate, acetonitrile, dimethylsulfoxide, or dimethylformamide. Preferably, the first solvent includes, but is not limited to, atleast one of ethylacetate, acetone, tetrahydrofuran, dimethylcarbonate,acetonitrile, toluene, xylene, methanol, ethanol, isopropanol,dimethylsulfoxide, or dimethylformamide. More preferably, the firstsolvent is at least one of ethylacetate, methanol, acetonitrile, ordimethylformamide. When two solvents are used, the ratio of solvents ispreferably about 90 to about 10 by volume, or about 95 to about 5 byvolume.

Before addition of the hydrochloric acid, the first slurry may becooled, preferably at a temperature of about 10° C. to about −20° C.,and more preferably at about 0° C. to about 2° C. The reaction may becarried out at temperatures of about −10° C. to about 40° C.

The HCl may be added as a solution or a gas. For example, methods foradding HCl include, but are not limited to, adding aqueous HCl (37%),HCl gas, HCl in at least one C₁-C₄ alcohol, or HCl in dimethylformamide.Typically, when present as a solution in an alcohol, the HCl is presentin 5% concentration. Typically, HCl is added in an amount of about 1 molto about 1.3 mol equivalents of the (R)-SLB.D-DBTA, and preferably about1.2 mol equivalent.

The crude levalbuterol hydrochloride is isolated by filtration andpreferably washed with additional portions of the first solvent prior topreparation of the second slurry.

When present, the second solvent for preparing the second slurryincludes, but is not limited to, at least one linear or branched C₃-C₆ester, C₃-C₁₀ ketone, C₃-C₁₀ ether, C₁-C₄ alcohol, C₆-C₁₂ aromatichydrocarbon, dimethylcarbonate, dimethylformamide, dimethylsulfoxide,dichloromethane, or acetonitrile. Preferably, the second solvent is atleast one of methanol, ethanol, isopropanol, ethylacetate, butylacetate, DMF, acetone, toluene, isopropyl ether, diethyl ether, methyltert butyl ether, dichloromethane, or acetonitrile. Water may be addedto the second solvent, preferably with acetone.

The slurry may be carried out at a temperature of about −10° C. to aboutthe reflux temperature of the second solvent. The second slurry may becarried out at room temperature, or about 20° C. to about 25° C. Thelevalbuterol hydrochloride is preferably isolated by filtration andwashed with additional portions of the second solvent. Optionally, thelevalbuterol hydrochloride is dried, such as at room temperature underreduced pressure.

In a preferred embodiment, the first and second solvents may be anester, an alcohol, or a combination thereof. For example, the first orsecond solvent is a C₃-C₆ ester or a mixture of a C₁-C₄ alcohol and aC₃-C₆ ester. C₃-C₆ Esters include, but are not limited to, at least oneof methylacetate, ethylacetate, isopropyl acetate, butyl acetate, orisobutyl acetate. The preferred ester is ethylacetate. C₁-C₄ Alcoholsinclude, but are not limited to, at least one of methanol, ethanol,propanol, or butanol. Methanol is the preferred alcohol. When the firstsolvent is a mixture, the alcohol to ester ratio is preferably about15:85 by volume, and more preferably about 5:95 by volume. When thesecond solvent is a mixture, the alcohol to ester ratio is preferablyabout 15:85 by volume, and more preferably about 1:9 by volume.

The above described process may prepare enantiomerically purelevalbuterol hydrochloride by the use of enantiomerically pure(R)-SLB.D-DBTA as a starting material. For example, the levalbuterolhydrochloride is prepared by forming a first slurry of enantiomericallypure (R)-SLB.D-DBTA in a first solvent.

The invention also encompasses levalbuterol hydrochloride degradationproducts useful for identifying impurities within an levalbuterolhydrochloride sample. Isolated levalbuterol hydrochloride degradationproducts may be used to quantify an impurity content of a levalbuterolhydrochloride sample. A sample of levalbuterol hydrochloride may bespiked with a known amount of the degradation product and analyzed byHPLC to identify the impurities. An impurity level can be determined bycomparing the area percent by HPLC of a known impurity with the areapercent of the corresponding standard impurity injected in a knownamount within linearity range. When levalbuterol is prepared withmethanol, benzylic and secondary alcoholic functional groups undergoetherification to produce the following impurities:

One degradation product isN-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(hydroxymethyl)phen-1-yl-ethanamine,or Compound B:

Another degradation product isN-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(methoxymethyl)phen-1-yl)-ethanamine,or Compound C:

The invention further encompasses levalbuterol hydrochloride having lowresidual alcohol content and/or a stabilizing pH in aqueous solution. Ithas been found that residual alcohol content and/or pH affect thestability of levalbuterol over time.

The levalbuterol hydrochloride made by the processes described abovetypically has less than about 1700 ppm of residual C₁-C₄ alcohol.Preferably, the levalbuterol hydrochloride has 1600 ppm or less residualC₁-C₄ alcohol. Preferably, the residual alcohol is methanol. Table 1exemplifies the effect of the first solvent used during thetransformation of (R)-SLB.D-DBTA in hydrochloride on the residualalcohol content of the final product. For the examples of Table 1, thesecond solvent is a mixture of methanol:ethylacetate at 1:9 by volume.

TABLE 1 First solvent and residual methanol content. First solventResidual Example (volume ratio) MeOH (ppm) 1 AcOEt-MeOH 85-15 5500 2AcOEt-MeOH 90-10 5300 3 AcOEt-MeOH 90-10 7000 4 AcOEt-MeOH 90-10 6700 5AcOEt-MeOH 92.5-7.5 1950 6 AcOEt-MeOH 95-5 1300 7 AcOEt-MeOH 95-5 1700 8AcOEt-MeOH 95-5 1470 9 AcOEt-MeOH 95-5 1500 10 AcOEt-MeOH 95-5 1160 11AcOEt-MeOH 95-5 1270 12 AcOEt 700 13 AcOEt 878 14 AcOEt 640 15 AcOEt 620

Table 1 illustrates that the alcohol present in the first solvent has aneffect on residual alcohol in the product. For example, if the ratio ofester to alcohol is 95:5 or higher, then the levalbuterol hydrochloridewith a residual alcohol content has less than about 1700 ppm of residualalcohol.

In another embodiment, the levalbuterol hydrochloride has a pH of atleast about 4.3 in 1% aqueous solution at room temperature. Preferably,the pH is about 4.5 to about 7. The effect of residual alcohol contentand pH on the stability of levalbuterol hydrochloride when stored at 70°C. is exemplified in Table 2. Preferably, the levalbuterol hydrochlorideof the invention has less than about 1600 ppm or less of residual C₁-C₄alcohol and a pH of at least about 4.3 in 1% aqueous solution at roomtemperature.

TABLE 2 Stability of levalbuterol hydrochloride at 70° C. Total CompoundCompound Compound Unknown MeOH Sample Time LVB^(a) A B C ImpuritiespH^(b) (ppm) White solid T = 0 99.9% 0.05% 0.02% n.d. 0.04% 4.41 300White solid 1 week 99.8% 0.06% 0.02% n.d. 0.04% White solid T = 0 99.8%0.03% 0.02% n.d. 0.10% 5.30 1500 White solid 1 week 99.7% 0.10% 0.06%0.03% 0.07% White solid^(c) T = 0 99.4% 0.24% 0.18% 0.15% n.d. 3.97 3420Pale yellow 1 week 97.1% 0.72% 0.26% 0.18% 1.21% solid White solid T = 099.8% 0.04% 0.05% n.d. 0.06% 3.70 700 Yellow solid 1 week 98.9% 0.22%0.06% 0.05% 0.45% White solid T = 0 99.8% 0.02% 0.01% n.d. 0.12% 3.50878 Yellow solid 1 week 93.1% 0.27% 0.08% 0.07% 4.72% ^(a)Levalbuterolhydrochloride. ^(b)Measured at 22-23° C. in 1% aqueous solution.^(c)Made according to Example 21.

Table 2 demonstrates that pH and/or residual alcohol content affect thedegradation of levalbuterol hydrochloride and/or the presence ofdegradation products Compounds A, B, C, or other impurities. At similarpH values, samples with greater residual alcohol content resulted inhigher levalbuterol hydrochloride degradation. At lower pH values,greater levalbuterol hydrochloride degradation occurred. In addition, itwas observed that samples with high residual methanol content or low pHvalues after storage for 1 week at 70° C. became yellow, whereas sampleswith low residual methanol content and a pH of at least about 4.3remained as white solids. The effect of storage temperature on thestability of levalbuterol hydrochloride is illustrated in Table 3.

TABLE 3 Stability of levalbuterol hydrochloride at 40-45° C., 50-55° C.,and 25° C. T Compound Compound Total Unknown MeOH Sample Time (° C.) LVBB A Impurities (ppm) 1 T = 0 20° C. 99.84% 0.035%  0.028%  0.097%  67002 20 hrs 40-45° C.   99.30% 0.30% 0.11% 0.29% — 3 20 hrs 55-60° C.  98.17% 0.45% 0.23% 1.15% — 4 32 hrs 55-60° C.    97.9% 0.45% 0.26% 1.39%— 5 T = 0 25° C. 99.90% 0.01% 0.02% 0.07% 2090 6 10 days 25° C. 99.88%0.01% 0.02% 0.09% — 7 1 month 25° C. 99.87% 0.02% 0.03% 0.08% — 8 2months 25° C. 99.82% 0.02% 0.04% 0.12% —

Table 3 illustrates that greater levalbuterol hydrochloridedecomposition occurred at elevated storage temperatures. The inventionencompasses levalbuterol hydrochloride where the amount of each ofCompound A, Compound B, or Compound C after storage for three months at40° C. and 75% relative humidity is less than about 0.15% by area HPLC.The percentage LVB, Compound B, or Compound A is relative to the totalamount of sample at time=T.

In another embodiment, the levalbuterol hydrochloride has total amountof unknown impurities after storage for three months at 40° C. and 75%relative humidity of less than about 0.10% by area HPLC. The term“unknown impurities” refers to any impurity in the sample other thanCompound A, Compound B, or Compound C.

The invention also encompasses levalbuterol hydrochloride where thetotal amount of impurities including Compound A, Compound B, andCompound C after storage for three months at 40° C. and 75% relativehumidity is less than about 1% by area HPLC.

Levalbuterol hydrochloride having at least one of the impurity profilesdescribed above preferably has less than about 1700 ppm of residualC₁-C₄ alcohol and/or a pH of at least about 4.3 in 1% aqueous solutionat room temperature and/or less than 1% of impurities. Preferably, thelevalbuterol hydrochloride has less than 0.5% of impurities.

The invention encompasses pharmaceutical compositions comprising atleast one levalbuterol hydrochloride of the invention and at least onepharmaceutically-acceptable excipient. The pharmaceutical compositionmay contain a single levalbuterol hydrochloride polymorphic form, amixture of various crystalline forms, and/or the amorphous form.

Any excipient commonly known and used widely in the art can be used inthe pharmaceutical composition. The excipients included in thecomposition are determined primarily by the manner in which thecomposition is to be administered. For example, a composition to beadministered in inhalant form can include a liquid carrier and/orpropellant. A composition to be administered in tablet form can includea filler (e.g., lactose), a binder (e.g., carboxymethyl cellulose, gumarabic, gelatin), an adjuvant, a flavoring agent, a coloring agent, or acoating material (e.g., wax or a plasticizer). A composition to beadministered in liquid form can include, for example, an emulsifyingagent, a flavoring agent and/or a coloring agent.

The pharmaceutical composition comprising the levalbuterol hydrochloridecan be administered by inhalation, by subcutaneous or other injection,orally, intravenously, topically, parenterally, transdermally, rectallyor via an implanted reservoir containing the drug. The form in which thedrug will be administered (e.g., inhalant, powder, tablet, capsule,solution, emulsion) will depend on the route by which it isadministered.

If a conflict exists between a compound's nomenclature and chemicalstructure, the chemical structure will define the compound. While theinvention is described with respect to particular examples and preferredembodiments, it is understood that the invention is not limited to theseexamples and embodiments. The invention as claimed therefore includesvariations from the particular examples and preferred embodimentsdescribed herein, as will be apparent to one of skill in the art.

EXAMPLES

Yields were determined by mass. Chemical purity was determined by HPLC.The HPLC analysis was conducted using a column POLARIS C18-A 250 mm×4.6mm×5.0 mm (cat n.2002−250×046) and a mobile phase. The mobile phasecomprised a phosphate buffer at pH 3.00 and acetonitrile in a gradient.The eluent flow was 1.0 ml/min. The detector was set to a wavelength of230 nm, using an HPLC Hewlett Packard VWD detector HP 1100, as adetector.

Enantiomeric excess was determined by HPLC using a chiral column. Thecolumn and packing was a CHIREX S-indoline-carboxylicacid-R-α-naphtylethylamine 250 mm×4.60 mm (Phenomenex cat. N̂00G-3022-EO)and the diluent was a mobile phase. The mobile phase was a mixture ofn-hexane: CH₂Cl₂: MeOH:CF₃COOH (500:440:60:0.4 by volume, respectively).Each chromatogram was run for to 20 minutes. The column temperature was25° C. and the flow rate was 1.5 ml/min. The detector was set to UV at280 nm.

The X-Ray diffraction (XRD) analysis was conducted using an ARL X-Raypowder diffractometer (model X′TRA-030) equipped with a Peltierdetector, round standard aluminum sample holder with round zerobackground, and quartz plate. The scanning parameters were from a rangeof about 2-40 degree two 0 (+0.2 degrees) and a continuous scan at arate of about 3 degrees/min. One of ordinary skill in the artunderstands that experimental differences may arise due to differencesin instrumentation, sample preparation, or other factors.

Fourier transform infrared (FT-IR) spectroscopy was conducted using aPerkin-Elmer Spectrum 1000 Spectrometer at about 4 cm⁻¹ resolution withabout 16 scans in the range of 4000-400 cm⁻¹. Samples were analyzed inKBr pellet and the instrument was calibrated using an empty cell as abackground.

Differential scanning calorimetry (DSC) was conducted using a MettlerToledo DSC 822^(e)/700 with a sample weight of about 3-5 mg, a heatingrate of about 10° C./min., using a 3 holed crucible, under a stream ofN₂ at a flow rate of about 40 ml/min. The sample was scanned between arange of about 30° C. to about 250° C. at a heating rate of about 10°C./minute.

Thermal Gravimetric Analysis (TGA) was conducted using a Mettler ToledoTGA/SDTA 851^(e) using a sample weight of about 7-15 mg, a heating rateof about 10° C./min. under a N₂ stream at a N₂ flow rate of about 50ml/min. The samples were scanned at a range between about 30° C. toabout 250° C.

Example 1 Preparation of crude (R)-SLB.D-DBTA, or (R)(−)α¹-[[(1,1Dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate.

In a 2 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at 20° C. and under nitrogen, salbutamol base (200 g), D-DBTA(150 g), and methanol (900 mL) were loaded. The temperature increasedfrom 20° C. to 32° C. to form a solution. The solution was cooled to 25°C., and a second portion of D-DBTA (150 g) was loaded. The solution washeated to 60-63° C. The solution was cooled to 50° C. and seeded withpure (R)-SLB.D-DBTA (enantiomeric excess >99%, 0.350 g). Precipitationformed, and the mixture was maintained at 50° C. for 30 min, cooled to−5° C.±2° C. in 2 hours, and maintained at the temperature for 2 hoursafter which a solid appeared. The solid was collected by filtration andwashed with cold methanol (2×100 mL).

Crude (R)-SLB.D-DBTA was obtained as a wet solid (319.14 g). The wetproduct was crystallized according to the procedure described in Example2.

Example 2 Preparation of pure (R)-SLB.D-DBTA, or (R)(−)α¹-[[(11Dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate.

In a 1 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at room temperature and under nitrogen, a suspension of wet(R)-SLB.(D)-DBTA (Loss on Drying 21.7%, 319.14 g) in methanol (660 mL)was formed. The suspension was heated to light reflux (62-63° C.) untila solution formed. The solution was cooled at 60° C., and treated withcharcoal (2.5 g). After 15 min at 60-62° C. the charcoal was filteredoff while the solution was maintained at 60-62° C. to avoidcrystallization.

The filtrate, a clear solution, was cooled at 50° C. to obtain crystals.The solution was maintained at 50° C. for 30 min, cooled to −5° C. in 2hours, and maintained at the temperature for 3 hours. The solid wascollected by filtration and washed with cold methanol (160 mL) andethylacetate (3×160 mL) to obtain a wet solid (253.6 g). The wet solidwas dried for 24 hours at 20-25° C. under vacuum to obtain pure(R)-SLB.D-DBTA (dry 213.5 g).

The crystallization yield was 87.6%. The overall yield from racemicsalbutamol was 42.7%. The enantiomeric excess of pure (R)-SLB.D-DBTA was99.8%.

Example 3 Preparation of Crude Levalbuterol Hydrochloride

In a 2 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at room temperature and under nitrogen, a suspension of pure(R)-SLB.D-DBTA (150 g, 0.25 mol), ethylacetate (1710 mL), and methanol(90 mL) was formed. The suspension was cooled to 0° C.±2° C., and HCl(37%, 29.44 g, 0.30 mol) was added in about 15 minutes. The temperaturewas maintained at 0° C.±2° C. The suspension was stirred at 0° C.±2° C.for 1 hour. The solid was collected by filtration and washed with anethylacetate:methanol mixture (95:5, 80 mL), followed by washing withethylacetate (2×80 mL).

The wet product (97.6 g) was slurried according to the proceduredescribed in Example 4.

Example 4 Preparation of Pure Levalbuterol Hydrochloride

In a 2 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at 20° C. and under nitrogen, a suspension of wet levalbuterolhydrochloride (97.6 g), ethylacetate (440 mL) and methanol (49 mL) wasformed. The suspension was stirred at 22° C.±2° C. for 4 hours. Thesolid was collected by filtration and washed with anethylacetate:methanol mixture (90:10, 97 mL), and ethylacetate (2×97mL). The product was dried at 22° C.±2° C. under vacuum (res. press.40-45 mm Hg) for 24 hours to obtain 64.0 g (dry weight) in 92.5% yieldfrom pure (R)-SLB.D-DBTA. The overall yield from racemic salbutamol topure levalbuterol hydrochloride: 39.5%.

Example 5 Preparation of crude (R)-SLB.D-DBTA, or(R)(−)α¹-[[(1,1Dimethylethyl)amino]methyl]-benzenedimethanol.(D-Dibenzoyltartrate

In a 10 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at 20° C. and under nitrogen, salbutamol base (800 g), D-DBTA(400 g), and methanol (3600 mL) were loaded. The temperature increasedfrom 20° C. to 26° C. A second aliquot of D-DBTA (400 g) was loaded andthe temperature increased to 31° C. A third aliquot of D-DBTA (400 g)was loaded, the temperature increased to 32° C. and a solution wasobtained. The solution was heated to 60-63° C. The solution was cooledto 50° C. and seeded with pure (R)-SLB.D-DBTA (enantiomeric excess >99%,1.404 g). The mixture was maintained at 50° C. for 30 min, then thesolution was cooled to −7° C.±2° C. in 2 hours, and maintained at thetemperature for 2 hours. The solid was collected by filtration andwashed with cold (−5° C.) methanol (2×400 mL). Crude (R)-SLB.D-DBTA wasobtained as a wet solid (1255 g, LOD=23.7% corresponding to 950 gYield=47.5%). HPLC purity=99.5%. Optical purity: R-levalbuterol vsS-levalbuterol=95.8:4.2. The wet product was crystallized according tothe procedure described in Example 6.

Example 6 Preparation of pure (R)-SLB.D-DBTA, or(R)(−)α¹-[[(1,1-dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate

In a 4 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at room temperature and under nitrogen, a suspension of wet(R)-SLB.(D)-DBTA (1245 g; LOD=23.7%, 950 g) in methanol (2477 mL) wasformed. The suspension was heated to gentle reflux (62-63° C.) until asolution formed. The solution was cooled to 60° C., and treated withcharcoal (9.5 g). After 15 min at 60-62° C. the charcoal was filteredoff while the solution was maintained at 60-62° C. to avoidcrystallization.

The filtrate, a clear solution, was cooled at 50° C. to obtain crystals.The solution was maintained at 50° C. for 30 min, cooled to −8° C. in 2hours, and maintained at the temperature for 3 hours. The solid wascollected by filtration and washed with cold methanol (607 mL) andethylacetate (3×588 mL) to obtain a wet solid (1061.8 g, assay=78.4%corresponding to 832 g dry). The crystallization yield was 87.6%. Theoverall yield from racemic salbutamol was 41.6%. HPLC purity=99.5%;Optical purity: R-levalbuterol vs S-levalbuterol=99.88:0.12

Example 7 Preparation of Crude Levalbuterol Hydrochloride

In a 10 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at room temperature and under nitrogen, a suspension of pure(R)-SLB.D-DBTA (823 g, 1.378 mol), ethylacetate (9180 mL), and methanol(490 mL) was formed. The suspension was cooled to 0° C.±2° C., and HCl(37%, 161 g, 1.634 mol) was added in 30 minutes. The temperature wasmaintained at 0° C.±2° C. The suspension was stirred at 0° C.±2° C. for1 hour. The solid was collected by filtration and washed with anethylacetate:methanol mixture (95:5, 435 mL), followed by washing withethylacetate (2×438 mL). 419.3 g of wet crude levalbuterol hydrochloridewere obtained. HPLC purity=99.6%. The wet product (419.3 g) was slurriedaccording to the procedure described in Example 8.

Example 8 Preparation of Pure Levalbuterol Hydrochloride

In a 4 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at 20° C. and under nitrogen, a suspension of wet crudelevalbuterol hydrochloride (414.3 g), ethylacetate (2398 mL) andmethanol (267 mL) was formed. The suspension was stirred at 22° C.±2° C.for 4 hours. The solid was collected by filtration and washed with anethylacetate:methanol mixture (90:10, 533 mL), and ethylacetate (2×533mL). The product was dried at 25° C. under vacuum (res. press. 40-45 mmHg) for 24 hours to obtain 357.3 g (dry weight) in 93% yield from pure(R)-SLB.D-DBTA. The HPLC purity=99.87%; compound A=0.01%; compoundB=0.03%; compound C=n.d. Total Unknown Impurities=0.09%; HPLC assay:100.3%; Optical purity: R-levalbuterol vs S-levalbuterol=99.9:0.1 byHPLC; e.e. =99.8; pH=4.41; Residual solvents: EtOAc 880 ppm, MeOH 300ppm, EtOH 65 ppm, and CH₃COOH 160 ppm.

Example 9 Preparation of crude (R)-SLB.D-DBTA, or (R)(−)α¹-[[(1,1Dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate.

In a 3 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at 20° C. and under nitrogen, salbutamol base (265 g), D-DBTA(199 g), and methanol (1190 mL) were loaded. The temperature increasedfrom 20° C. to 35° C. The mixture was cooled to 28° C. A second portionof D-DBTA (199 g) was loaded and the suspension was heated to 60-63° C.The solution was cooled to 50° C. and seeded with pure (R) —SLB.D-DBTA(enantiomeric excess >99%, 0.46 g). The mixture was maintained at 50° C.for 30 min, cooled to −5° C. in 2 hours, and maintained at thetemperature for 1.6 hours. The solid was collected by filtration andwashed with cold methanol (2×139 mL).

Crude (R)-SLB.D-DBTA was obtained as a wet solid (395 g; LOD=22%corresponding to 308 g of dry product; yield=46.5%). HPLC purity=99.0%;Optical purity: R-levalbuterol vs S-levalbuterol=97.3:2.7. The wetproduct was crystallized according to the procedure described in Example10.

Example 10 Preparation of pure (R)-SLB.D-DBTA, or(R)(−)α¹-[[(1,1-dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate.

In a 2 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at room temperature and under nitrogen, a suspension of wet(R)-SLB.(D)-DBTA (395 g; LOD=22%, 308 g dry) in methanol (815 mL) wasformed. The suspension was heated to gentle reflux (62-63° C.) until asolution formed. The solution was cooled to 60° C., and treated withcharcoal (3 g). After 15 min at 60-62° C. the charcoal was filtered offwhile the solution was maintained at 60-62° C. to avoid crystallization.

The filtrate, a clear solution, was cooled at 50° C. to obtain crystals.The solution was maintained at 50° C. for 30 min, cooled to −8° C. in 2hours, and maintained at the temperature for 2 hours. The solid wascollected by filtration and washed with cold methanol (197 mL) andethylacetate (3×191 mL) to obtain a wet solid (336.4 g; assay=82.3%corresponding to 277 g of dry product). The crystallization yield was89.9%. The overall yield from racemic salbutamol was 41.8%. HPLCpurity=99.0%; Optical purity: R-levalbuterol vs.S-levalbuterol=99.9:0.1.

Example 11 Preparation of Crude Levalbuterol Hydrochloride

In a 4 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at room temperature and under nitrogen, a suspension of pure(R)-SLB.D-DBTA (wet=331 g; assay=82,3%; 0.4559 mol), ethylacetate (3060mL), and methanol (163 mL) was formed. The suspension was cooled to 0°C.±2° C., and HCl (37%, 53.7 g, 0.545 mol) was added in 30 minutes. Thetemperature was maintained at 0° C.±2° C. The suspension was stirred at0° C.±2° C. for 1 hour. The solid was collected by filtration and washedwith an ethylacetate:methanol mixture (95:5, 146 mL), followed bywashing with ethylacetate (2×146 mL). The wet product (137.5 g; 122 gdry) was slurried according to the procedure described in Example 12.HPLC purity=99.6%; Optical purity: R-levalbuterol vsS-levalbuterol=99.92:0.08.

Example 12 Preparation of Pure Levalbuterol Hydrochloride

In a 4 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at 20° C. and under nitrogen, a suspension of wet levalbuterolhydrochloride (133 g), ethylacetate (799 mL) and methanol (89 mL) wasformed. The suspension was stirred at 22° C.±2° C. for 4 hours. Thesolid was collected by filtration and washed with anethylacetate:methanol mixture (90:10, 178 mL), and ethylacetate (2×178mL). The product was dried at 25° C. under vacuum (res. press. 40-45 mmHg) for 24 hours to obtain 116 g (dry weight) in 92.3% yield from pure(R)-SLB.D-DBTA.

HPLC purity=99.91%; compound A=0.02%; compound B=0.01%; compound C=n.d.;Total Unknown Impurity=0.06%; HPLC assay: 100.3%; Optical purity:R-levalbuterol vs S-levalbuterol=99.93:0.07 by HPLC; e.e. =99.86;pH=4.86; Residual solvents: EtOAc 830 ppm; MeOH 430 ppm; EtOH 56 ppm;and CH₃COOH 152 ppm.

Example 13 Preparation of crude (R)-SLB.D-DBTA, or (R)(−)α¹-[[(1,1Dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate.

In a reactor equipped with a condenser, thermometer, and mechanicalstirrer at 20° C. and under nitrogen, salbutamol base (44 Kg), D-DBTA(66 g, added in three portions), and methanol (200 L) were loaded. Thetemperature was kept below 32° C. The mixture was heated to 60-63° C.for 30′. The solution was cooled to 50° C. and seeded with pure(R)-SLB.D-DBTA (enantiomeric excess >99%, 0.08 Kg). The mixture wasmaintained at 50° C. for 30 min, cooled to −7° C.±2° C. in 2 hours and15 minutes, and maintained at the temperature for 2 hours. The solid wascollected by filtration and washed with cold (−5° C.) methanol (2×44 L).Crude (R)-SLB.D-DBTA was obtained as a wet solid (67.9 Kg, LOD=20.5%corresponding to 53.98 Kg). The wet product was crystallized accordingto the procedure described in Example 14.

Example 14 Preparation of pure (R)-SLB.D-DBTA, or(R)(−)α¹-[[(1,1-dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate.

In a reactor equipped with a condenser, thermometer, and mechanicalstirrer at room temperature and under nitrogen, a suspension of wet(R)-SLB.(D)-DBTA (67.9 Kg wet; 53.98 Kg dry) in methanol (140 L) wasformed. The suspension was heated to light reflux (62-63° C.) until asolution formed. The solution was cooled to 60° C., and treated withcharcoal (2 Kg) and dicalite (3 Kg). After 15 min at 60-62° C. thecharcoal was filtered off while the solution was maintained at 60-62° C.to avoid crystallization; the filter was washed with hot methanol (10L).

The filtrate, a clear solution, was cooled at 50° C. to obtain crystals.The solution was maintained at 50° C. for 30 min, cooled to −5° C. in2.5 hours, and maintained at the temperature for 2 hours 15 min. Thesolid was collected by filtration and washed with cold methanol (32 L)and ethylacetate (3×100 L) to obtain a wet solid (54 Kg, assay=85.5%corresponding to 46.2 Kg dry product).

Example 15 Preparation of Crude Levalbuterol Hydrochloride

In a reactor equipped with a condenser, thermometer, and mechanicalstirrer at room temperature and under nitrogen, a suspension of pure(R)-SLB.D-DBTA (45.3 Kg), ethylacetate 517 L), and methanol (22 L) wasformed. The suspension was cooled to 0° C.±2° C., and HCl (37%, 9.2 Kg)was added in 30 minutes. The temperature was maintained at 0° C.±2° C.The suspension was stirred at 0° C.±2° C. for 1.5 hour. The solid wascollected by filtration and washed with an ethylacetate:methanol mixture95:5 (23 L), followed by washing with ethylacetate (2×25 L). The wetproduct (24.2 Kg) was slurried according to the procedure described inExample 16. HPLC purity=99.8%.

Example 16 Preparation of pure levalbuterol hydrochloride

In a reactor equipped with a condenser, thermometer, and mechanicalstirrer at 20° C. and under nitrogen, a suspension of wet levalbuterolhydrochloride (24.2 Kg), ethylacetate (156 L) and methanol (15 L) wasformed. The suspension was stirred at 22° C.±2° C. for 4.5 hours. Thesolid was collected by filtration and washed with an ethylacetate:methanol mixture (90:10, 30 L), and ethylacetate (2×30 L). The productwas dried at 22° C. under vacuum for 18 hours to obtain 17.9 Kg (dryweight) of pure levalbuterol hydrochloride. HPLC purity=99.86%; compoundA=0.01%; compound B=0.02%; compound C=n.d.; Total UnknownImpurity=0.11%; HPLC assay: 100.3%; Optical purity: R-levalbuterol vsS-levalbuterol=99.9:0.1 by HPLC; e.e. =99.8; pH=5.30; Residual solvents:EtOAc 480 ppm; MeOH 1600 ppm; EtOH 180 ppm; and CH₃COOH 170 ppm.

Example 17 Stability Comparison of Sample at 40° C. and 75% RH

Using the products of the previous examples, a stability study at 40° C.and 75% RH was carried out. Table 4 summarizes the results.

TABLE 4 Stability Comparison of Sample at 40° C. and 75% RH Exam. Comp.Comp. Comp. Total Unknown MeOH No. Time LVB A B C Impurities (ppm) pH 8T = 0 99.87% 0.01% 0.03% n.d. 0.09% 300 4.41 8 3 months 99.85% 0.03%0.07% n.d. 0.05% — 8 6 months 98.81% 0.03% 0.07% n.d. 0.09% — 12 T = 099.91% 0.02% 0.01% n.d. 0.06% 430 4.86 12 3 months 99.85% 0.02% 0.06%n.d. 0.07% — 12 6 months 99.83% 0.02% 0.06% n.d. 0.09% — 16 T = 0 99.86%0.01% 0.02% n.d. 0.11% 1600  5.30 16 3 months 99.75% 0.06% 0.09% 0.04%0.08% — 16 6 months 99.72% 0.07 0.13% 0.05% n.d. —

Example 18 Preparation of crude (R)-SLB.D-DBTA, or(R)(−)α¹-[[(1,1-Dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate.

In a 10 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at 20° C. and under nitrogen, salbutamol base (1257 g), D-DBTA(1887 g, in three portions), and methanol (5657 mL) were loaded. Thetemperature was kept below 32° C. The mixture was heated to 60-63° C.and a solution was obtained, which was cooled to 50° C. and seeded withpure (R)-SLB.D-DBTA (enantiomeric excess >99%, 2.2 g). The mixture wasmaintained at 50 C for 30 min, cooled to −7° C.±2° C. in 2 hours, andmaintained at the temperature for 2 hours. The solid was collected byfiltration and washed with cold (−5° C.) methanol (2×627 mL). Crude(R)-SLB.D-DBTA was obtained as a wet solid (1879 g, LOD=19%corresponding to 1522 g dry). The wet product was crystallized accordingto the procedure described in Example 19. Optical purity: R-levalbuterolvs S-levalbuterol=96.9:3.1.

Example 19 Preparation of pure (R)-SLB.D-DBTA, or(R)(−)α¹-[[(1,1-dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate.

The solid obtained in example 18 was divided in two portions, each wastreated as reported below.

In a 5 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at room temperature and under nitrogen, a suspension of wet(R)-SLB.(D)-DBTA (747 g) in methanol (2019 mL) was formed. Thesuspension was heated to gentle reflux (62-63° C.) until a solutionformed. The solution was cooled to 60° C., and treated with charcoal(7.4 g). After 15 min at 60-62° C. the charcoal was filtered off whilethe solution was maintained at 60-62° C. to avoid crystallization. Thecake was washed twice with hot methanol (77 ml).

The filtrate was cooled at 50° C. to obtain crystals. The solution wasmaintained at 50° C. for 30 min, cooled to −8° C. in 2 hours, andmaintained at the temperature for 3 hours. The solid was collected byfiltration and washed with cold methanol (478 mL) and ethylacetate(3×462 mL) to obtain a wet solid (810 g, assay=79.8% corresponding to646 g dry). The crystallization yield was 86.5%. Optical purity:R-levalbuterol vs S-levalbuterol=99.8:0.2.

Example 20 Preparation of Crude Levalbuterol Hydrochloride

In a 10 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at room temperature and under nitrogen, a suspension of pure wet(R)-SLB.D-DBTA (810 g), ethylacetate (7174 mL), and methanol (388 mL)was formed. The suspension was cooled to 0° C.±2° C., and HCl (36%, 130g) was added in 15 minutes. The temperature was maintained at 0° C.±2°C. The suspension was stirred at 0° C.±2° C. for 1 hour. The solid wascollected by filtration and washed with an ethylacetate:methanol mixture(95:5, 344 mL), followed by washing with ethylacetate (2×334 mL). Thewet product (406 g) was slurried according to the procedure described inExample 21. HPLC purity=99.9%. Optical purity: R-levalbuterol vsS-levalbuterol=99.8:0.2.

Example 21 Preparation of Pure Levalbuterol Hydrochloride

In a 10 L reactor equipped with a condenser, thermometer, and mechanicalstirrer at 20° C. and under nitrogen, a suspension of wet levalbuterolhydrochloride (846.7 g), ethylacetate (3810 mL) and methanol (423 mL)was formed. The suspension was stirred at 22° C.±2° C. for 4 hours. Thesolid was collected by filtration and washed with anethylacetate:methanol mixture (90:10, 821 mL), and ethylacetate (2×821mL). The product was dried at 22° C. under vacuum (res. press. 40-45 mmHg) for 18 hours to obtain 580 g (dry weight) in 40% yield from racemicsalbutamol. HPLC purity=99.82%; compound A=0.07%; compound B=0.04%;compound C=n.d.; Total Unknown Impurity=0.06. %; HPLC assay: 99%;R-levalbuterol:S-levalbuterol=99.8:0.2 by HPLC; e.e. =99.6%; pH=3.97;Residual solvents: EtOAc 870 ppm; MeOH 3420 ppm; and EtOH 490 ppm.

1-22. (canceled)
 23. Levalbuterol hydrochloride characterized by atleast one of an enantiomeric excess of at least about 99.8%; having lessthan about 1700 ppm of residual C₁-C₄ alcohol; or having a pH of atleast about 4.3 in 1% aqueous solution at room temperature.
 24. Thelevalbuterol hydrochloride according to claim 23, wherein the residualalcohol is methanol.
 25. The levalbuterol hydrochloride according toclaim 23, wherein the pH is about 4.5 to about
 7. 26. Levalbuterolhydrochloride characterized by at least one of having less than about0.15% by area HPLC of at least one of Compound A, Compound B, andCompound C; having less than about 0.10% by area HPLC of total unknownimpurities; or having less than about 0.25% by area HPLC of eachimpurities including Compound A, Compound B, and Compound C, after beingstored for three months at 40° C. and 75% relative humidity. 27-28.(canceled)
 29. A pharmaceutical composition comprising a therapeuticallyeffective amount of the levalbuterol hydrochloride according to claim 26and at least one pharmaceutically-acceptable excipient.